Amyloid accumulating diseases include a variety of diseases characterized by the deposition of insoluble fibrillary proteins (amyloids) in various organs and tissues in the body, including Alzheimer's disease, Down's syndrome and others. Among them, Alzheimer's disease (AD) is considered as a disease which is most difficult to treat at present, and there is a need for its accurate and early diagnosis.
Alzheimer's disease (AD) is considered as a disease which is most difficult to treat at present and whose accurate and early diagnosis is required. Alzheimer's disease is a disease whose feature is progressive dementia developing predominantly in a presenile to senile period. Alzheimer's disease is pathologically characterized by overall cerebral atrophy, remarkable degeneration and neuronal loss, and appearing of neurofibrillary tangles and senile plaques. It is known that the highest risk factor of dementia represented by Alzheimer's disease is aging. Thus, an increase in the number of patients as an old population increases is remarkable in especially Japan, America, and European countries, which have reached an aging society, and medical costs for the patients bring the medical system of those countries to a crisis.
In Japan, it is estimated that the number of patients with Alzheimer's disease are about one million, and it is certain that the number of the patients will increase with the aging of the population in future. The costs associated with Alzheimer's disease patients, including the nursing care expense, are supposed to exceed 2.5 million yen per patient for a year, which means that in Japan, socioeconomic costs more than 2.5 trillion yen have been already paid for a year. It has now become common in the world that significant effects of medical economy will be brought about by administering treatment before symptoms of dementia in Alzheimer's disease become appeared or as early as possible. At present, however, it is extremely difficult to make an accurate diagnosis of Alzheimer's disease at these stages.
Currently there are various types of methods for diagnosing Alzheimer's disease. Japan commonly employs methods which make a quantitative evaluation of the decrease in cognitive functions of an individual suspected to be affected with Alzheimer's disease, such as Hasegawa's procedure, ADAS, and MMSE, and although not often, imaging diagnosis methods (MRI, CT, and others) are employed supplementarily. However, these methods are insufficient to define the disease, and its definitive diagnosis requires biopsy of the brain before death or histopathological examinations of the brain after death. In spite of these intensive studies on methods for diagnosing Alzheimer's disease, progress has been not made so much. From results of many studies, it has turned out that neural degeneration characteristic of Alzheimer's disease has already took place for a considerable period of time (about 40 years, in the case of a long period) prior to developing its initial clinical symptom. In addition, it is known for Alzheimer's disease that the pathologic feature in the brain has already progressed to an irrecoverable stage when family members and clinicians surrounding an AD patient recognize its initial clinical symptom. Considering together the progression properties of disease conditions and a sharp increase in the number of AD patients as described above, the need for and the value of an accurate, early diagnosis of Alzheimer's disease are of extreme significance.
The histopathological feature of Alzheimer's disease is represented by two major signs: senile plaques and neurofibrillary tangles. The former has, as the main component, amyloid β-protein (Aβ protein) taking β-sheet structures, whereas the latter has, as the main component, hyperphosphorylated tau protein. The definite diagnosis of Alzheimer's disease relies on the appearance of these pathological characteristics in the brain of a patient.
Amyloid β-protein is characteristic of diseases in which amyloid accumulates, including Alzheimer's disease, and has a close relation with the disease. Thus, detection of amyloid β-protein taking β-sheet structures in the body, especially in the brain, as a marker, will provide for an important method for the diagnosis of a disease in which amyloid accumulates, particularly Alzheimer's disease. In the past, substances which can bind specifically to and stain amyloid β-protein in the body, especially in the brain, have been searched for the purpose of diagnosing diseases in which amyloid accumulates, including Alzheimer's disease. Such substances known include Congo red (Puchtler et al., Journal of Histochemistry and Cytochemistry, vol. 10, 35, 1962), thioflavin S (Puchtler et al., Journal of Histochemistry and Cytochemistry, vol. 77, 431, 1983), thioflavin T (LeVine, Protein Science, vol. 2, 404–410, 1993), and chrysamine G and derivatives thereof (International Patent Application Nos. PCT/US96/05918 and PCT/US98/07889), and they have not a few problems in terms of binding specificity to amyloid β-protein, permeability through the blood-brain barrier, solubility, toxicity, and others. The present inventors have found a variety of compounds characterized by having high specificity to amyloid β-protein, high permeability through the blood-brain barrier, high solubilities, reduced toxicities, and others (Japanese Patent Application Nos. 2000-080082, 2000-080083, and 2001-076075, and International Patent Application Nos. PCT/JP01/02204 and PCT/JP01/02205).
It is known that intracerebral proteins may take β-sheet structures, thereby resulting in diseases whose etiology can be assigned to such proteins themselves. In the case of Alzheimer's disease, it is supposed that amyloid β-protein and tau protein take β-sheet structures, whereby such proteins themselves are responsible for or contribute to the disease. Yankner et al. have first reported that amyloid β-protein is allowed to take β-sheet structures, thereby displaying neural cytotoxicity (Science, vol. 245, 417–420, 1989). Later, many experiments for corroboration have been performed and ascertained that amyloid β-protein with β-sheet structures possess neural cytotoxicity. Thus, the fact that neural cytotoxicity is observed with amyloid β-protein and tau protein taking β-sheet structures suggests that compounds inhibiting their cytotoxicity could be drugs for treating a disease in which a protein itself takes β-sheet structures, thereby causing or contributing to the disease, for example, Alzheimer's disease.
Neurofibrillary tangles and their main component, hyperphosphorylated tau protein, which are another histopathological major sign of Alzheimer's disease, are generally supposed to develop later than amyloid β-protein. However, it is likely that neurofibrillary tangles correlate well with the degree of dementia, compared to amyloid β-protein (Braak H and Braak E: Acta Neuropathol., vol. 82, 239–259, 1991; Wischik et al., In “Neurobiology of Alzheimer's Disease,” 103–206, Oxford University Press, Oxford, 2001).
Besides Alzheimer's disease, disorders whose major sign is accumulation of tau protein in the brain (tauopathies) include Pick's disease, progressive supranuclear palsy (PSP), and others.
As mentioned above, tau protein is characteristic of diseases in which tau protein accumulates, including Alzheimer's disease, and has a close relation with the disease. Thus, detection of tau protein taking β-sheet structures in the body, especially in the brain, as a marker, will provide for an important method for the diagnosis of a disease in which tau accumulates, particularly Alzheimer's disease.
Methods have been reported by a few groups for quantifying tau in the body, especially in the cerebrospinal fluid for the purpose of diagnosing diseases in which tau accumulates, including Alzheimer's disease (Ishiguro et al., Neurosci. Lett., vol. 270, 81–84, 1999 and Itoh et al., Ann. Neurol., vol. 50, 150–156, 2001). However, no probe intended to quantify tau noninvasively in vivo can be found throughout the world.
Therefore, there is an increased need for compounds having high specificity to tau which is for the diagnosis and treatment of diseases in which tau accumulates, including Alzheimer's disease.
On the one hand, studies of Alzheimer's disease or diagnoses employing biopsy or autopsy samples until now involve preparation of brain sections from a patient with Alzheimer's disease and staining them. Conventional staining agents have mainly utilized Congo red or thioflavin S. These staining agents are characterized by staining both senile plaques and neurofibrillary tangles, which are said to be two major pathological signs of Alzheimer's disease.
However, none of many reports so far reports low molecular-weight organic compounds capable of staining only neurofibrillary tangles.